1. Field of the Invention
This application relates generally to the identification and measurement of geographic atrophy, and more specifically, to the identification of geographic atrophy in ophthalmic optical coherence tomography applications.
2. Description of Related Art
In ophthalmic and other applications, optical coherence tomography (OCT) is frequently used to generate three-dimensional scan data of a volume. OCT scans typically utilize one of relatively few fixation positions—most commonly the macula or optic disc, which place the respective feature at or near the center of the OCT scan. Wide scan patterns, which cover a large area that encompasses both the macula and optic disc, are also increasingly popular. A single scan in the axial dimension generates a depth profile (an “A-line” or “A-scan”), while a series of A-scans along a given line generate a B-scan. A series of B-scans can then be used to form the 3D volume.
In certain diseases of the back of the eye—such as geographic atrophy (GA), choroideremia, retinitis pigmentosa, glaucoma, and multiple sclerosis (MS)—there are rough patterns of tissue atrophy that may present as either or both of: (1) changes in thickness; and (2) changes in OCT reflectivity values (image pixel intensities). Changes in thickness tend to result in thinning of the affected tissues with disease progression; however, less common retinal diseases related to inflammation can cause an increase in thickness. Diseases including GA, choroideremia, and retinitis pigmentosa involve atrophy of a layer or layers in the outer retina and/or surrounding tissue layers such as the retinal pigment epithelium (RPE), outer segments, inner segments, and/or choriocapillaris. Glaucoma and MS typically involve atrophy of the retinal nerve fiber layer (rNFL) and ganglion cell layer (GCL). Changes in OCT reflectivity values typically result from or are associated with a change in tissue attenuation properties, sometimes in a different tissue layer than the one being measured or observed. Alternatively and spuriously, decreases in reflectivity can result from increased shadowing (darkening, reducing the dynamic range of data) associated with lens crystallizations (cataracts) or floaters in the vitreous. Relatively large measurable changes are more associated with certain tissue layers and with certain retinal locations than with others, and the nature of these is highly disease specific.
Geographic atrophy, also called advanced ‘dry’ age-related macular degeneration (AMD), causes substantial and progressive visual impairment, developing in approximately 20% of patients presenting with preexisting clinical signs of AMD. GA is characterized by confluent areas of apoptosis at the level of photoreceptors and RPE atrophy, occurring bilaterally in more than half of patients affected. The condition progresses slowly over time, typically sparing the fovea until the later stages of disease progression. The atrophy can be unifocal (one atrophic spot) or multifocal (multiple spots).
Clinical trials to evaluate new therapies for non-neovascular AMD require reliable, accurate, and simple means of monitoring GA size and progression. Accurately monitoring GA progression can also help to better understand the pathogenesis of GA and AMD in general, as numerous aspects of AMD pathogenesis are not particularly well understood at present.
In choroideremia, the choriocapillaris (small capillary vessels in the choroid just outer to the Bruch's membrane), the RPE, and photoreceptors (in the later stages of disease) degenerate leading to lost visual function over time. As with GA, a visible thinning of the RPE can often be observed in affected areas in OCT scans. Additionally, due to decreased attenuation of the RPE layer (primarily of the RPE complex, though also of the choriocapillaris and possibly other tissue features, such as the photoreceptors), the signal in the choroid and beyond (e.g., the sclera) appears relatively bright in OCT scans.
Retinitis pigmentosa is a progressive retinal disease that affects the photoreceptors resulting in a severe loss of vision. Atrophy can be observed in the outer segments (OS) of receptor and other layers, such as the outer nuclear layer (ONL). Usually the thinning of the OS layer precedes changes in other receptor layers. In the case of RP, the visible thinning of the OS, possibly the RPE, ONL, and total retinal thickness can be observed with the NFL layer intact or even thicker.
There are four main processes in age-related macular degeneration pathogenesis, which preferentially affects the macula. In the first, lipofuscin formation, RPE metabolic insufficiency associated with aging leads to progressive accumulation of lipofuscin granules (a roughly even mixture of lipids and proteins) in the RPE. This is also related to failure to clear some metabolites from outer segment phagocytosis from the RPE. A lipofuscin component known as A2E is known to be a cytotoxic molecule, capable of generating free radicals, damaging DNA, etc.
Next, drusen formation is the result of extracellular deposits collecting between the RPE and Bruch's membrane. While most elderly individuals have a small number of “hard” drusen, the presence of numerous “hard” or “soft” drusen (especially the soft variety, which are typically larger in area), particularly when accompanied by pigment changes, is thought to be an early indicator of AMD. Drusen formation is also thought to relate to inflammatory processes as well as CFH gene allele Y402H.
The third process, chronic local inflammation, is not very well understood and is tied to lipofuscin and drusen formation, as well as additional factors including light irradiation and genetics, including the CFH gene allele Y402H,
Finally, neovascularization (wet AMD) is distinct from geographic atrophy. Neovascularization is thought to be preceded either by hypoxia or inflammation (or a combination of the two), leading to a signaling pathway that triggers an increased production of VEGF (vascular endothelial growth factor), which precipitates choroidal neovascularization.
Geographic atrophy is generally considered to be the non-wet end-stage of AMD, although some consider GA to be the default end-stage of advanced AMD. It should be noted, however, that both GA and wet AMD can occur together in the same eye. In GA, the RPE and outer segments atrophy in affected regions, and the atrophy typically extends to surrounding tissue layers as well, including the inner segments, the outer nuclear layer, and possibly the choriocapillaris. Associated with the loss of retinal function, blind spots (scotomas) result in the patient's central vision.
Traditional imaging modalities, fundus imaging and fundus autofluorescence imaging, have been used to detect GA. In fundus imaging, GA is defined as a sharply demarcated area exhibiting an apparent absence of the RPE, with visible choroidal vessels and no neovascular AMD. Fundus autofluorescence imaging is based on the autofluorescence properties of AMD-related compounds, such as lipofuscin, that build up in RPE cells. Fundus autofluorescence imaging is probably the most widely applied technique with respect to GA detection at present.
In an emerging OCT technique, GA is associated with increased OCT signal intensities in the choroidal region (i.e., outer to the Bruch's membrane), which arises from the absence of the RPE, other parts of the outer retina, and possibly the choriocapillaris. The RPE and choriocapillaris are two tissue layers, hyperreflective in OCT scans, that normally cause the incident light to scatter, thus partially preventing deeper transmission of light (and therefore OCT signal) into the choroid. OCT allows cross-sectional visualization that permits image readers to characterize microstructural alterations in the different laminae of the retina. Using only one type of scan for documenting both en face and cross-sectional images of the retina, it can therefore provide more detailed insight in retinal alterations of GA patients than fundus autofluorescence imaging.
However, there are a number of problems with current techniques for quantifying GA. For example, techniques that rely on simple signal integration only indirectly address the physical phenomenon of decreased attenuation that is actually occurring. Similarly, techniques based on signal integration are subject to multiple types of signal shadowing: (1) beneath retinal blood vessel locations (though vessel sizes tend to be small in the macula); and (2) from cataracts, in which entire areas could be affected. Such methods also utilize spectral domain OCT (SD-OCT) with an 800nm wavelength. It should be noted that 800nm light is significantly more affected by cataracts than light with longer wavelengths. The intensity of signal that is significantly attenuated (e.g., 800nm signal in the choroid or sclera) can be artificially elevated by the OCT system's noise floor. As a technique, this will serve to increase measurement variability and reduce methodological sensitivity/specificity. For the sub-RPE slab technique, the complexity of the OCT signal in the choroid can lead to some degree of randomness in the integrated signal and resulting analysis. The inner choroid, including the choriocapillaris and Sattler's layer, includes many high intensity pixels, but with great variation both in intensity and spatially. The outer choroid, consisting of Haller's layer, comprises many pixels of lower intensity corresponding to large blood vessels, but the size (both in terms of width and thickness) and spacing of such vessels can vary widely. Meanwhile, full OFI techniques (signal summation over a full A-line) are subject to noises related to inner retinal signals that are completely independent of AMD phenotypes. These deficiencies can produce complexities that make it difficult for image processing algorithms to effectively and robustly detect atrophic regions.
In addition to the above, ANSI, and possibly other standards organizations as well, places safety limits on the maximum power density that can be applied to the ocular surfaces such as the cornea and retina. This means that there is an effective limit with respect to the achievable sensitivity for in vivo ocular imaging. With this in mind, it is not possible to arbitrarily increase the light power in order to achieve any desired signal intensity at deeper retinal positions.